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BRaf and MEK inhibitors differentially regulate cell fate and microenvironment in human hepatocellular carcinoma

Christian Breunig1, Bernadett J Mueller, Ludmila Umansky

  • 1Authors' Affiliations: Division of Molecular Genome Analysis B050, German Cancer Research Center (DKFZ); Immunomonitoring Unit, National Center for Tumor Diseases (NCT) at the DKFZ; Department of Translational Immunology, DKFZ and NCT; Department of General, Visceral and Transplantation Surgery, University Hospital, Heidelberg; Institute of Transplant Immunology, OE8889, IFB-Tx; Departments of Gastroenterology, Hepatology and Endocrinology; and Abdominal and Transplantation Surgery, Hannover Medical School, Hannover, Germany.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|February 28, 2014
PubMed
Abstract

Insights

Small molecule inhibitors targeting the mitogen-activated protein kinase (MAPK) pathway impact hepatocellular carcinoma cell fate and microenvironment signaling. These findings suggest novel biomarkers for predicting treatment response to MAPK inhibitors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Small molecule inhibitors targeting the mitogen-activated protein kinase (MAPK) pathway, like sorafenib, offer new therapeutic avenues for advanced hepatocellular carcinoma (HCC).
  • Identifying downstream targets linked to the oncogenic MAPK pathway is crucial for developing predictive biomarkers in HCC treatment.

Purpose of the Study:

  • To identify downstream targets of the MAPK pathway in HCC that can serve as biomarker candidates.
  • To correlate these targets with the inhibition of the MAPK pathway by multikinase inhibitors.

Main Methods:

  • Hepatocellular carcinoma cell lines and patient-derived tissues were treated with BRAF or MEK inhibitors.
  • Analysis included kinase phosphorylation, cell proliferation, apoptosis induction, and chemokine secretion.

Main Results:

  • Differential dose-dependent responses to inhibitors were observed in HCC cell lines, irrespective of BRAF/NRAS mutations.
  • MAPK inhibitors affected cell proliferation, apoptosis, and significantly altered chemokine secretion.
  • Patient-derived tissues mirrored the cellular responses, showing microenvironmental changes.

Conclusions:

  • MAPK pathway signaling influences HCC sensitivity to BRAF and MEK inhibitors, impacting cell fate independently of specific mutations.
  • MAPK inhibitors profoundly affect chemokine secretion, highlighting its role in treatment response.
  • Biomarkers within the HCC microenvironment hold potential for predicting and monitoring therapeutic outcomes.

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